6697 Prostate-Specific Membrane Antigen (PSMA) Expression in Cytologically Indeterminate and Malignant Thyroid Nodules

Abstract Disclosure: R. Sadiq: None. J.O. Russell: Consulting Fee; Self; Baxter. Grant Recipient; Self; Eli Lilly & Company. Research Investigator; Self; Eli Lilly & Company. P.W. Ladenson: Consulting Fee; Self; Veracyte, Inc., Viking Therapeutics. M. Alshalalfa: Employee; Self; Veracyte, Inc.. Stock Owner; Self; Veracyte, Inc. Y. Hao: Employee; Self; Veracyte, Inc.. Stock Owner; Self; Veracyte, Inc. J. Huang: Employee; Self; Veracyte, Inc.. Stock Owner; Self; Veracyte, Inc. J.P. Klopper: Employee; Self; Veracyte, Inc.. Stock Owner; Self; Veracyte, Inc. R.T. Kloos: Employee; Self; Veracyte, Inc.. Stock Owner; Self; Veracyte, Inc. P. Santhanam: Consulting Fee; Self; Carelon Rx. Prostate-specific membrane antigen (PSMA), a transmembrane protein encoded by the gene FOLH1 is a relatively novel target for molecular imaging and therapy in prostate cancer imaging. PSMA-based positron-emission tomography (PET) imaging is approved and recommended in the United States for biochemical recurrence after prostate cancer treatment. This receptor is often expressed on the cell membrane of neovascular endothelial cells of a variety of solid tumors. Immunohistochemical studies reported that several thyroid cancer (TC) subtypes, including papillary and follicular, with intense PSMA staining in the neovasculature had more clinically aggressive behavior than TC with weak PSMA expression. Here we aimed to characterize the expression of PSMA in a large cohort of thyroid nodules. FOLH1 (PSMA) mRNA expression was analyzed across 47,695 thyroid nodules sent for Afirma Genomic Sequencing Classifier (GSC) molecular testing. Differential PSMA expression was explored across Afirma benign and suspicious categories, Bethesda cytology categories, and relative to different molecular alterations identified by the Afirma Xpression Atlas. There were 30,259 cytologically indeterminant nodules classified as GSC-Benign (GSC-B) and 15,815 as GSC-Suspicious (GSC-S); 1,621 were cytologically Bethesda V or VI. Mean expression of PSMA gene was higher in GSC- S and Bethesda V/VI nodules compared to GSC-B (Wilcoxon p-value < 2e-[1]6 for both). Relative to GSC-B, GSC-S and Bethesda V/VI had fold changes (FC) of 1.12 and 1.2, respectively. PSMA expression was higher in Bethesda VI compared to Bethesda V (p=5e-7). Compared to GSC-B, GSC-S samples with PAX8-PPARG, ALK/RET fusions had higher PSMA expression (FC 1.57, 1.28 respectively, p<2e-[1]6 for both). Within Bethesda V/VI nodules, PSMA was higher in samples with PPARG fusions (CREB3L2-PPARG, PAX8-PPARG), ALK, or RET fusions compared to other alterations (p= 0.002). Samples with TSHR variants had the lowest PSMA expression in both GSC-S and Bethesda V/VI samples (FC 1.06, 1.03 respectively with respect to GSC-B). Finally, a negative trend was observed between PSMA and sodium iodide symporter (NIS) expression with samples with highest PSMA having the lowest NIS expression. In conclusion, PSMA expression in indeterminate and malignant thyroid nodules varies across cytology groups and in the presence of different molecular alterations. PSMA expression may provide further thyroid tumor prognostic information in the context of cytology and associated molecular variants. The basis for increased PSMA expression in the setting of PPARG and other fusions is an opportunity for future investigation, as are the roles of preoperative assessment of PSMA expression and PSMA-based imaging and therapy in the setting of advanced thyroid cancer. Presentation: 6/3/2024